1 Introduction
Schizophrenia is a chronic and serious mental disorder characterized by positive and negative symptoms, as well as cognitive impairment. Disease onset is typically between the ages of 15 and 35 years; in these individuals, social functioning and the ability to work are impaired. Schizophrenia is a global public health problem [1] as it requires repeated treatments, with many patients experiencing residual symptoms. Therefore, better strategies for the treatment of schizophrenia are urgently needed.
Despite substantial progress in the pharmacotherapy of schizophrenia, a subset of patients are treatment-resistant. Electroconvulsive therapy (ECT) can ameliorate schizophrenia and is typically administered under anesthetic along with a muscle relaxant; blood pressure is closely monitored, and an electrocardiogram is performed concomitantly. Under these conditions, there is no muscular response (convulsion) and the electroencephalogram is near normal. ECT is an effective treatment for various psychiatric illnesses and is the first-choice, non-pharmacological treatment after conventional pharmacologic interventions have failed; it is often used in treatment-resistant schizophrenia and recurrent refractory mania [Reference Pompili, Lester, Dominici, Longo, Marconi and Forte2], and is safe and cost-effective [Reference Rodriguez-Jimenez, Bagney, Torio, Caballero, Ruiz and Rivas3].
Little is known about the etiology and pathogenesis of schizophrenia. One hypothesis posits that the disease is secondary to a dysregulation of neurotrophic factor levels during brain development, which could lead to disorganization of neuronal networks. Inadequate neurotrophic support in the adult brain may decrease its capacity to adapt to changes and increase vulnerability to neurotoxic damage. Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that is widely expressed in the central and peripheral nervous systems and plays a major role in the survival and maintenance of dopaminergic neurons and synaptic plasticity [Reference Gao, Wang, Mao, Graff, Guan and Pan4]. Deficits in BDNF production and utilization have been implicated in the pathology of schizophrenia [Reference Angelucci, Brene and Mathe5, Reference Kim, Song, So, Lee, Song and Kim6]; it has been shown that BDNF induces the short-term release of dopamine [Reference Goggi, Pullar, Carney and Bradford7].
Human studies have reported reductions in BDNF levels in the serum [Reference Akyol, Albayrak, Beyazyuz, Aksoy, Kuloglu and Hashimoto8] and dorsolateral prefrontal cortex [Reference Reinhart, Bove, Volfson, Lewis, Kleiman and Lanz9] of patients with schizophrenia as compared to healthy controls; this was confirmed in a meta-analysis of medicated and drug-naive patients [Reference Leucht10]. Reports on BDNF levels in schizophrenia are inconsistent. For instance, Gama et al. reported that chronically medicated schizophrenia patients exhibited higher BDNF levels than controls [Reference Gama, Andreazza, Kunz, Berk, Belmonte-de-Abreu and Kapczinski11]. Peripheral BDNF levels in schizophrenia decreased with disease progression and were increased by treatment with antipsychotic medication [Reference Leucht10]. Chronic administration of clozapine was shown to be effective in treating patients with schizophrenia; BDNF levels have been shown to be correlated with clozapine dose [Reference Pedrini, Chendo, Grande, Lobato, Belmonte-de-Abreu and Lersch12]. In addition, electroconvulsive seizures were reported to induce an increase of BDNF mRNA [Reference Nordgren, Karlsson, Svensson, Koczy, Josephson and Olson13] and protein [Reference Segawa, Morinobu, Matsumoto, Fuchikami and Yamawaki14] levels in rat brain.
BDNF levels are reduced in drug-naïve first-episode schizophrenia and are increased by antipsychotic treatment [Reference Leucht10], suggesting that they can be normalized by pharmacotherapy. We conjectured that ECT may also alter serum BDNF levels when improving clinical symptoms of schizophrenia. To test the hypothesis, we measured serum concentrations of BDNF in schizophrenia patients receiving ECT.
2 Methods
2.1 Study population
A total of 160 patients with schizophrenia were recruited for the study. Written, informed consent was obtained from participants or their caregivers. Diagnosis was based on DSM-IV criteria and all patients were interviewed in person by a trained psychiatrist. The ECT group consisted of 80 patients (38 female, 42 male; mean age: 38.1 ± 11.1 years, range: 17–60 years) who were referred for ECT at the Department of Psychiatry, WuTaiShan Hospital, Yangzhou, China; all of these patients were treated with antipsychotics. The drug therapy group included 80 patients (36 female, 44 male; mean age: 37.7 years, range: 16–65 years) who received only antipsychotic drug treatment at the hospital. The control group consisted of 77 healthy individuals without a history of psychiatric disorders. Exclusion criteria were as follows: hypothyroidism, epilepsy, diabetes, or cardiovascular disorders. The study protocol was approved by the local Institutional Ethics Committee.
2.2 ECT
All subjects underwent standard clinical evaluation prior to ECT. Pre-medication in all patients consisted of 0.05 mg atropine sulfate, 1.0 mg/kg propofol, and 1.0 mg/kg succinylcholine by intravenous injection. Patients underwent bilateral ECT between 07:00 and 09:00 h; a Thymatron TMDG instrument was used (Somatics, Lake Bluff, IL, USA). Two stimulus electrodes were placed on the left and right frontotemporal scalp. ECT conditions were similar for all patients (maximum charge delivered = 504 mC; output current = 0.9 A; frequency = 10–70 Hz; pulse width = 0.5 ms; and maximum stimulus duration = 8 s). Motor convulsions and induced tachycardia were monitored and electroencephalogram and electromyogram (when necessary) were recorded during ECT, which was administered 8–10 times every other day.
2.3 Symptom ratings
A trained research assistant or psychologist administered the Positive and Negative Syndrome Scale (PANSS) to all participants with schizophrenia to obtain a measure of current symptom severity. Patients recommended for ECT treatment were examined twice: before starting ECT and within 3 days after completing the sessions. Patients treated only with antipsychotic drugs were also examined twice: before starting antipsychotic treatment and after completing 8 weeks of treatment.
2.4 BDNF assay
After overnight fasting, pre-prandial blood samples were collected between 08:00 and 09:00 h on the same schedule as for symptom assessment. For healthy controls, a baseline blood sample was collected on the morning of the first visit. For patients receiving ECT, a baseline blood sample was collected on the morning of the first session and post-treatment serum was obtained within 3 days of the last session. Serum samples were separated by centrifugation (3000 rpm for 10 min at 20 °C) and stored at −80 °C. BDNF concentration was measured with an enzyme-linked immunosorbent assay (Emax Immunoassay System kit; Promega, Madison, WI, USA) according to the manufacturer's instructions.
2.5 Statistical analysis
Differences in continuous variables between groups were assessed by the independent samples t-test; the χ 2 test was applied to categorical data such as gender. The paired samples t-test was used to evaluate changes in PANSS score and BDNF level. The relationship between the two variables was examined using Spearman's correlation coefficient. P-values < 0.05 were considered statistically significant.
3 Results
3.1 Demographic data
Demographic and clinical characteristics of the study population are summarized in Table 1. There were no differences in demographic data (gender and age) between groups. Serum BDNF levels in patients are shown in Fig. 1 All patients included in the ECT group received antipsychotic treatment, including aripiprazole (n = 32), quetiapine (n = 26), olanzapine (n = 4), risperidone (n = 3), or a combination of antipsychotics (n = 15). Mean antipsychotic dose (chlorpromazine equivalent) was 443 ± 217 mg/day [Reference Melkerson15]. In the medication group, patients were treated with aripiprazole (n = 34), quetiapine (n = 21), olanzapine (n = 8), risperidone (n = 3), or a combination of antipsychotics (n = 14). Mean antipsychotic dose (chlorpromazine equivalent) was 440 ± 224 mg/day (Table 2).
Table 1 Characteristics of schizophrenia patients and healthy controls.
a Chi-square test.
b independent samples t-test.
c paired samples t-test.
d BDNF in controls > before MECT or medication.
e BDNF in controls compared with after MECT or medication.
f BDNF in before MECT or medication < after MECT or medication.
Fig. 1 Serum levels of BDNF in controls, before and after treatments. Results are means with S.D.
Table 2 Antipsychotics used by schizophrenia patients (number of cases).
a Independent samples t-test.
3.2 ECT group
There were no correlations between PANSS scores and serum BDNF levels before ECT; however, a negative correlation was observed after ECT (total: r = −0.692, P < 0.01; positive: r = −0.602, P < 0.01; negative: r = −0.362, P < 0.01; general: r = −0.573, P < 0.01, Fig. 2A). At the end of the study, mean serum BDNF concentration was 11.9 ± 3.3 ng/ml and mean PANSS score was 54.6 ± 14.9 in patients (Table 1). From baseline to remission after ECT, serum BDNF level increased (P < 0.001) and PANSS score decreased (P < 0.001) (Table 1). There was no difference in serum BDNF level between normal controls and patients after ECT (12.4 ± 3.2 ng/ml vs. 11.9 ± 3.3 ng/ml; P = 0.362). Changes in BDNF (2.21 ± 4.10 ng/ml) and PANSS score (28.69 ± 14.96) were positively correlated in the ECT group (r = 0.630, P < 0.01, Fig. 2B).
Fig. 2 (A) Association between BDNF levels and PANSS scores after treatments. (B) Association between changes in BDNF levels and improvement in PANSS scores following treatments. (C) Association between duration of illness and BDNF levels after treatments in 160 patients with schizophrenia.
3.3 Medication group
There were no significant correlations between PANSS scores and serum BDNF levels before treatment with medication; however, a negative correlation was observed after treatment (total: r = −0.521, P < 0.01; positive: r = −0.403, P < 0.01; negative: r = −0.473, P < 0.01; general: r = −0.273, P < 0.05, Fig. 2A). At the end of the study, mean serum BDNF was 11.7 ± 3.5 ng/ml and mean PANSS score was 49.4 ± 11.7 in patients (Table 1). From baseline to remission after drug treatment, serum BDNF level increased (P < 0.001) and PANSS score decreased (P < 0.001) (Table 1). There was no difference in serum BDNF level between normal controls and patients after medication (12.4 ± 3.2 ng/ml vs. 11.7 ± 3.5 ng/ml; P = 0.207). Changes in BDNF (1.93 ± 4.20 ng/ml) and PANSS score (24.80 ± 12.08) were positively correlated in the medication group (r = 0.286, P < 0.05, Fig. 2B).
3.4 Baseline BDNF levels in responders vs. non-responders
Among patients receiving ECT, 57/80 patients showed a decrease of 50% or more in total PANSS score and were therefore considered as responders [Reference Zakharyan and Boyajyan16]. In the ECT group, serum BDNF levels decreased in responders as compared to the levels in non-responders before treatment, but the difference was not statistically significant (9.6 ± 2.1 and 10.02.0 ng/ml, respectively; P = 0.431). It should be noted that we chose a cut off post hoc, and this altered the results [Reference Zakharyan and Boyajyan16]. There was also a significant difference in the sex ratio between responders and non-responders (male/female: 34/23 vs. 8/15; P < 0.05).
When the two groups were combined (n = 160), 116 patients showed a decrease of ≥50% in their PANSS total score and were considered as responders. There were no differences in demographic data (gender and age) between responders and non-responders. There was no difference in serum BDNF levels between responders and non-responders before treatment (9.8 ± 2.6 and 9.5 ± 2.6 ng/ml, respectively; P = 0.440). It also should be noted that we chose a cut off post hoc, which altered the results.
3.5 Association between BDNF level and length of illness
In the ECT group, there were no significant correlations between length of illness and serum BDNF levels before or after treatment (r = 0.015; P > 0.05 and r = −0.170; P > 0.05, respectively). This was also the case in the medication group (r = −0.063; P > 0.05 and r = −0.166; P > 0.05, respectively). When the groups were combined (n = 160), there was an inverse correlation between length of illness and serum BDNF levels, but only after treatment (r = −0.168; P < 0.05) (Fig. 2C).
4 Discussion
The results of this study show that serum BDNF level was lower in schizophrenia patients relative to healthy controls before ECT and medication. Furthermore, we observed an increase in BDNF level after ECT and medication, which paralleled PANSS improvement. This suggests that peripheral BDNF synthesis or release is reduced during acute episodes of schizophrenia [Reference Zakharyan and Boyajyan16, Reference Jindal, Pillai, Mahadik, Eklund, Montrose and Keshavan17], although it is not known whether this is a pathologic or compensatory effect. Our results are consistent with recent reports demonstrating that serum BDNF levels are lower in schizophrenia patients with deficit syndrome [Reference Akyol, Albayrak, Beyazyuz, Aksoy, Kuloglu and Hashimoto8] and that BDNF mRNA expression is downregulated in various cortical areas in schizophrenia [18–Reference Tunca, Kivircik Akdede, Ozerdem, Alkin, Polat and Ceylan20]. Some clinical studies recently reported a significant increase in BDNF transcript levels in peripheral mononuclear cells of schizophrenia patients following fluvoxamine augmentation of antipsychotics [Reference Silver, Mandiuk, Einoch, Susser, Danovich and Bilker21, Reference Silver, Susser, Danovich, Bilker, Youdim and Goldin22]. Here we found a significant negative correlation between serum BDNF level and PANSS score after ECT and medication.
It was previously shown that pre-treatment with risperidone protected PC12 cells from the cytotoxic effects of rotenone, a mitochondrial complex I inhibitor, and reversed rotenone-induced suppression of BDNF expression [Reference Tan, Wang, Wang, Liu, Chen and Wang23]. In rat hippocampal neuron cultures exposed to toxic agents, treatment with atypical antipsychotic drugs such as olanzapine, aripiprazole, quetiapine, and ziprasidone increased BDNF levels [Reference Park, Lee, Cho, Seo, Lee and Lee24]. In humans, stressful experiences during gestation or early in life have been linked to the occurrence of mental illness later in life [Reference Fumagalli, Molteni, Racagni and Riva25, Reference Szyf26]. Prenatal exposure to stress can cause long-term abnormalities in adult behavior in rats; in this model, treatment with the antipsychotic lurasidone abrogated the reduction in BDNF expression [Reference Luoni, Berry, Calabrese, Capoccia, Bellisario and Gass27].
Electroconvulsive seizures increase hippocampal neurogenesis [Reference Schloesser, Orvoen, Jimenez, Hardy, Maynard and Sukumar28] and angiogenesis [Reference Newton, Girgenti, Collier and Duman29] and enhance glial proliferation in the frontal cortex [Reference Ongur, Pohlman, Dow, Eisch, Edwin and Heckers30]. Serum BDNF levels are decreased in medicated and drug-free patients with schizophrenia [10,31,32], and altered BDNF levels have been implicated in the pathophysiology and treatment of schizophrenia [Reference Favalli, Li, Belmonte-de-Abreu, Wong and Daskalakis33, Reference Buckley, Pillai and Howell34]. BDNF levels were significantly lower in heroin-addicted patients with psychotic symptoms as compared to those without these symptoms [Reference Han, Zhang, Wang, Ren, Gu and Zhu35]. The Val66Met single nucleotide polymorphism in the BDNF gene has been linked to schizophrenia pathophysiology, symptoms, and treatment effects [36–Reference Krebs, Guillin, Bourdel, Schwartz, Olie and Poirier38]. It has also been shown that electroconvulsive seizures increase BDNF gene expression in various areas of rat brain [13,14,39].
We found a significant positive correlation between increased serum BDNF concentration and decreased PANSS score in both the ECT and medication groups, whereas a negative correlation between these variables was observed after ECT and medication. These findings are consistent with other reports, supporting a correlation between BDNF level and schizophrenia symptoms [40–Reference Reis, Nicolato, Barbosa, Teixeira do Prado, Romano-Silva and Teixeira42]. However, this correlation was not observed in a meta-analysis [Reference Leucht10]. The positive correlation between BDNF concentration and PANSS score suggests that increases in BDNF can predict the improvement in schizophrenia symptoms. In addition, various meta-analyses have demonstrated that BDNF levels are increased by antipsychotic medication [Reference Leucht10] or ECT [Reference Fernandes, Steiner, Berk, Molendijk, Gonzalez-Pinto and Turck43]. In other psychiatric disorders such as refractory depression, an increase in serum BDNF level is associated with the restorative effects of ECT [44–Reference Hu, Yu, Yang, Si, Wang and Tan46], while other studies have reported no changes in BDNF after ECT treatment [47–Reference Rapinesi, Kotzalidis, Curto, Serata, Ferri and Scatena49]. Our results suggest that ECT induces an increase in serum BDNF levels in schizophrenia. One explanation for the underlying mechanism is that increases in BDNF concentration enhance dopamine synthesis and turnover; this is supported by the finding that BDNF plays a major role in the survival and maintenance of dopaminergic neurons and synaptic plasticity [4,50,51].
A limitation of this study is that patients undergoing ECT were treated with antipsychotics; as such, the effect of medications on laboratory test results needs to be considered. Future studies should address the influence of repeated doses of medication over multiple ECT cycles on BDNF level and schizophrenia symptoms. The major advantage of this study is the large sample size; this is the first study carried out in 80 schizophrenia patients undergoing ECT.
5 Conclusion
The results of this study showed that serum BDNF levels increased in schizophrenia patients following ECT, suggesting a mechanism by which ECT improves schizophrenia symptoms. These findings also provided evidence that BDNF contributes to the pathophysiology of schizophrenia, and that changes in BDNF level may be a good index for evaluating the antipsychotic effects of ECT.
Disclosure of interest
The authors declare that they have no competing interest.
Acknowledgements
This study was supported by Shanghai Science and Technology Committee (15411967200 and 14411961400), and SHSMU-ION Research Center for Brain Disorders (2015NKX001) and Shanghai health system advanced appropriate technology (2013SY003).
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